Among 400,000 Americans who survive an ischemic stroke each year, a major source of morbidity and mortality is recurrent stroke and myocardial infarction. Within 5 years of the initial event, 25% of patients will have a recurrent stroke, 10% will have a myocardial infarction, and 12% will die from one of these two conditions. Prevention of further vascular events, therefore, is of major importance in reducing the morbidity and mortality of stroke. Current strategies for preventing vascular events after stroke include antiplatelet therapy, hypertension control, anticoagulation, lipid management, and carotid endarterectomy. Despite these effective strategies, many suitably-treated stroke patients still experience recurrent vascular events. New therapeutic approaches are urgently needed. The Insulin Resistance Intervention after Stroke (IRIS) trial proposes an innovative therapy based on 20 years of accumulating evidence linking insulin resistance to increased risk for stroke and other vascular diseases. The aim of the IRIS trial is to determine if pioglitazone, an agent that reduces insulin resistance and ameliorates associated pro-athrosclerotic events, is effective in lowering the risk for stroke or myocardial infarction among non-diabetic men and women with a recent ischemic stroke and insulin resistance. IRIS is a randomized, double-blind, placebo controlled trial that will enroll 3136 subjects at 101 hospitals. Eligible subjects will be at least 45 years of age. Insulin resistance will be defined using an index based on fasting insulin and glucose values. Recruitment will be completed in 3 years and all patients will be followed for a minimum of 3 years (average of 4). Assuming an outcome rate of 27% at 4 years for placebo recipients, IRIS has 90% power to detect a 20% reduction in risk for the primary endpoints of fatal and non-fatal stroke and myocardial infarction. The IRIS tdal will determine the effectiveness of a new strategy, the treatment of insulin resistance in non-diabetic subjects, for preventing recurrent stroke and myocardial infarction after ischemic stroke. Since insulin resistance is estimated to affect 50% of stroke patients, this innovative treatment has the potential to benefit a large number of patients. If effective, pioglitazone will be comparable to carotid endarterectomy for symptomatic disease or anticoacjulation for atrial fibrillation in terms of vascular events prevented.